L503F variant of carnitine/organic cation transporter 1 efficiently transports metformin and other biguanides.

OBJECTIVES: Carnitine/organic cation transporter 1 (OCTN1) is involved in gastrointestinal absorption and mitochondrial toxicity of biguanides in rodents, but its pharmacokinetic roles in humans are largely unknown. The purpose of this study was to clarify the transport activities of two major OCTN1 variants, L503F and I306T, for gabapentin and three biguanide drugs, metformin, buformin and phenformin. METHODS: HEK293 cells were transfected with OCTN1 gene, its variants, or vector alone, and the uptake and cytotoxicity of each drug were examined. KEY FINDINGS: Buformin was identified to be an OCTN1 substrate. Uptake of biguanides, especially metformin, mediated by OCTN1 variant L503F, which is commonly found in Caucasians, was much higher than that by the wild-type transporter (WT-OCTN1). Cytotoxicity of metformin was also greater in HEK293 cells expressing the L503F variant, compared with WT-OCTN1. Uptake of gabapentin mediated by OCTN1 variant I306T, which is commonly found in both Asians and Caucasians, was lower than that by WT-OCTN1, although uptake of the typical OCTN1 substrate ergothioneine was similar. CONCLUSION: Organic cation transporter 1 variant L503F transports biguanides, especially metformin, more efficiently than WT-OCTN1, whereas the I306T variant transports gabapentin less efficiently than WT-OCTN1, suggesting that the common OCTN1 variants may alter pharmacokinetics of these drugs.

Use of PKM-MULTI program for fitting discontinuous absorption profiles using a microcomputer.

The programs for the pharmacokinetic models with discontinuous absorption, written in BASIC, were connected to MULTI, which had been proposed for nonlinear least squares for a microcomputer by Yamaoka et al. Using this program (designated as PKM-MULTI), the same data sets previously calculated by HFCM, FITSI2 and NONLIN were fitted and the finally obtained estimates were in close agreement with those obtained previously. The plasma data of nalidixic acid were also fitted to the pharmacokinetic model with discontinuous absorption, which were suggested to be more valid compared with one compartment model with continuous absorption.

[Drug permeation through artificial lipid membranes. 17. The mechanism of ion pair transport]. / Arzneimittelpermeation durch künstliche Lipoidmembranen. 17. Mitteilung: Zum Mechanismus der lonenpaarpermeation.

The transport of ionized drugs across lipoid membranes can be increased considerable by lipophilic counter ions. This is caused by an increased lipophilicity of the ion pair which is formed between the ionized drugs and the lipophilic counterion. Caused by their very strong solubility in the membrane the lipophilic counterions accumulate and act like a carrier for the ionized drugs. Then the necessary compensation of the charges can take place by protons or other suitable ions of the used solution.

Use of metzler's NONLIN program for fitting discontinuous absorption profiles.

An alternative to the use of integral hybrid flow/compartmental model (HFCM) equations in fitting cases I and II discontinuous absorption profiles is presented. It is proposed that HFCM-integral equations be replaced by a system of differential equations in which sequential sets of equations describe the absorption profile from time zero to infinity. The required sets of differential equations for these two cases are presented as they apply to a two-compartment drug, potentially undergoing multiple absorption steps. It was shown that the use of the NONLIN program in the differential equation mode provides good fits for some unusually shaped absorption profiles of buformin, sulfisoxazole, and griseofulvin. The values of the parameter estimates and the sum of squared deviations, sigma SD, obtained with NONLIN were almost identical to those obtained with the FITS12 program utilizing HFCM equations. While HFCM-integral equations required less computer time, they introduced the potential for negative absorption times. This problem is avoided by use of the differential equations method.

[Drug permeation through synthetic lipid membranes. Part 13: The effects of tensides on the permeation of ionized drugs (author's transl)]. / Arzneimittelpermeation durch künstliche Lipoidmembranen. 13. Mitteilung: Einfluss von Tensiden auf die Permeation ionisierter Arzneistoffe.

The permeation of substances present in the ionized form is most markedly affected by tensides containing ions of opposite sign. These tensides produce a considerable increase in permeation. The effect of micelle formation will become evident only if the transport of the free drug through the membrane is more rapid than the release of the drug from the micelles. If the concentrations of nonionic tensides are less than the critical micelle concentration, a permeation increase occurs which is presumably caused by a reduction of the surface tension of the membrane.

[Drug interaction during therapy with tolbutamide. The influence of some commonly used drugs on plasma level and half life in diabetic out-patients (author's transl)]. / Arzneimittelwechselwirkungen bei der Therapie mit Tolbutamid Beeinflussung von Serumspiegel und Halbwertzeit durch einige gebräuchliche Pharmaka bei Altersdiabetikern.

Tolbutamide belongs to those drugs responsible for the majority of drug interactions. E.g. Tolbutamide metabolism has been shown to be inhibited by coumarole derivatives. We determined plasma-tolbutamide levels in diabetic out-patients for one year. The results obtained indicate no difference in patients additionally treated with either digoxin or digoxin and alpha-methyldopa, or buformin and phenprocumone as compared with control groups. Interactions with respect to biotransformation should not be expected as far as digoxin, alpha-Methyldopa, or buformine were concerned, since these compounds do not share a common metabolic pathway with tolbutamide. In a different group of patients the elimination half life of tolbutamide under the influence of phenprocoumone was additonally determined. Differences could not be detected. This finding can be explained by means of enzyme-kinetic considerations, since phenprocumone, in contrast to dicoumarole, becomes metabolized according to a first order reaction. Competitive enzyme inhibition with tolbutamide which is metabolized similarly to phenprocoumone, therefore appears improbable.

Discontinuous absorption processes in pharmacokinetic models.

The limited contact time of absorbable drug with absorbing surfaces is, in some cases, a significant factor determining the fraction of the dose absorbed. A simple modification of customary linear compartmental models is presented to account for this situation, and a general input function in the Laplace domain for truncated first-order absorption is derived. An extension to series of truncated absorption processes is discussed.

[Haemodialysis in the treatment of biguanide-induced lactate acidosis (author's transl)]. / Hämodialyse bei der Behandlung der biguanid-induzierten Lactacidose.

Severe lactate acidosis developed in nine diabetics on biguanide. When lactate acidosis was diagnosed all patients had reduced renal function, six being oligoanuric. Pre-existing chronic renal failure as a factor in the development of lactic acidosis was excluded in five patients, normal renal function being restored later. All patients were dialysed, seven surviving. This mortality rate is lower than that reported by others for biguanide-induced lactate acidosis. Rapid biguanide elimination by dialysis was demonstrated both in vitro and in vivo. The in vivo clearance of buformin was 83 +/- 43 ml/min (mean +/- SD, n = 4), that of phenformin 68 +/- 33 ml/min (n = 7). The main advantages of haemodialysis in the treatment of biguanide-induced lactic acidosis are rapid removal of toxic biguanides and excess lactate and the ability to administer sodium bicarbonate adequately without risking hypernatraemia and fluid overload.

[Distribution and excretion of 14c-butylbiguanide in man (author's transl)]. / Verteilung und Ausscheidung von 14C-Butylbiguanid beim Menschen.

Seven patients suffering from maturity on-set diabetes mellitus were given orally 100 mg of 14C-labelled butylbiguanide, specific activity 1.40 or 1.23 muCi/mg, resp. Three days before oral administration, two of the patients had received an i.v. injection of 50 mg butylbiguanide labelled with 120 muCi 14C. The radioactivity in the blood of the patients was followed up during the first 12-h period after administration of the drug. For determination of the radioactivity in the urine aliquots of three 24-h portions were measured. Furthermore, the radioactivity was checked of each individual sample of faeces for the first 72 h after administration. The radioactivity in the exhaled air was also measured. By comparison of the excretion after i.v. and oral application an absorption efficiency of 90% to 92% was calculated. Butylbiguanide is almost exclusively and fast excreted via the kidney. 86.5% of the i.v. administered material was eliminated within 24 h and 88.1% within 3 d in the urine of a person without kidney disease. Elimination through faeces was negligible, 0.2% in a person without kidney disease and 0.7% in a patient with renal insufficiency. The data obtained from the exhaled air show that there is only a negligible break-down of butylbiguanide, if any, to CO2 in man.